We previously discovered new aminoglycosidic antibiotics, istamycin A, istamycin B, istamycin A.sub.o and istamycin B.sub.o which are produced by Streptomyces tenjimariensis SS-939, a new strain of actinomycetes, deposited in the Japanese depository "Fermentation Research Institute" under the deposit number FERM P-4932 and also in American Type Culture Collection, U.S.A. under the deposit number ATCC 31603 (see Japanese patent application pre-publication "Kokai" No. 145697/80 and No. 43295/81; U.S. Pat. No. 4,296,106; published U.K. patent application GB 2048855A). Then, we synthesized 2"-N-formimidoyl derivatives of istamycins A and B (see published U.K. patent application GB No. 2088851; U.S. Pat. No. 4,382,926 issued May 10, 1983).
Subsequently, we totally synthetized di-N.sup.6',O.sup.3 -demethylistamycin A and found its antibacterial activity against Pseudomonas aeruginosa to be significantly higher than the parent istamycin A (see Japanese patent application pre-publication "Kokai" No. 138180/81; U.S. patent application Ser. No. 241,649; published U.K. patent application GB No. 2073182A). We then continued our studies on istamycin antibiotics with the intention of converting istamycin B (which has a higher antibacterial activity than istamycin A) into the 3-O-demethyl derivative thereof, and we succeeded in synthetizing 3-O-demethylistamycin B and 3-O-demethyl-2"-N-formimidoylistamycin B and have found that these 3-O-demethyl derivatives of istamycin B are active not only against Pseudomonas aeruginosa but also against a variety of resistant bacteria (see the "Journal of Antibiotics" 33, pp. 1577-1580 (December 1980); Japanese patent application pre-publication "Kokai" No. 50996/82; U.S. patent application Ser. No. 298,844; European patent application pre-publication No. 0048549A).
At this time, we have now succeeded in synthetizing new compounds, 3-demethoxyistamycin B and 3-demethoxy-2"-N-formimidoylistamycin B represented by the general formula (I) ##STR1## wherein R denotes a hydrogen atom for 3-demethoxyistamycin B and R denotes a formimidoyl group for 3-demethoxy-B 2"-N-formimidoylistamycin B, with employing as the starting material 3-O-demethylistamycin B.sub.o of the formula (II) ##STR2## which was formed as an intermediate product in the synthesis of the above-mentioned 3-O-demethyl derivatives of istamycin B (see the Japanese patent application pre-publication "Kokai" No. 50996/82; U.S. patent application Ser. No. 298,844, filed Sept. 3, 1981; European patent application pre-publication No. 0 048549A). We have now found that the new 3-demethoxy derivatives of istamycin B now synthetized by us strongly inhibit not only the growth of Pseudomonas aeruginosa but also the growth of gram-negative and gram-positive bacteria, including a wide variety of gram-negative and gram-positive bacterial strains which are resistant to known aminoglycosidic antibiotics. Thus, we have accomplished this invention.
In Japanese patent application pre-publication No. 164197/81 of Watanabe et al as the inventors (ensued from Japanese patent application No. 67084/80 filed May 22, 1980), there are disclosed a 5-demethoxy derivative of each of KA-6606I, KA-6606II, and KA-6606VI [the sporaricins, see "Journal of Antibiotics", 32, 187 (1979)]; and a 5-demethoxy-4-N-glycyl derivative of KA-6606VI; as well as a 5-demethoxy derivative of each of KA-7038I and KA-7038II [the sannamycins, see "Journal of Antibiotics", 30, 1066 (1979)]. These 5-demethoxy derivatives of the sporaricins and sannamycins are generically represented by the general formula ##STR3## wherein R.sub.1 and R.sub.2 may be the same or different and each is a hydrogen atom or a methyl group, and R.sub.3 is a hydrogen atom or an acyl group such as glycyl. The specification of the above Japanese patent application pre-publication "Kokai" No. 164197/81 contains at all no reference to istamycin B from which the new compounds of this invention are structurally derived. 3-Demethoxyistamycin B, one of the new compounds of this invention is clearly distinctive from the 5-demethoxy derivatives of sannamycins and sporaricins exemplified in the above-mentioned Japanese patent pre-publication "Kokai" No. 164197/81 in that the stereo configuration of the amino group at the 1-position of 3-demethoxyistamycin B and the nature of the substituent at the 6'-position of the 3-O-demethylistamycin B according to the general formula (I) are different from those of the 5-methoxy derivatives of the sannamycins and sporaricins, respectively, as this will be discussed later in more detail.
Further, in Japanese patent application pre-publication No. 7493/82 of Watanabe et al as the inventors (ensued from Japanese patent application No. 80842/80 filed June 17, 1980), there are disclosed 4-N-(N-formimidoylglycyl)derivative; 4-N-(N-formimidoylglycyl)-5-demethoxy derivative; and 4-N-(N-amidinoglycyl)-5-demethoxy-derivative of KA-6606II, as well as other analogues thereof which are generically represented by the general formula ##STR4## wherein R.sub.1 and R.sub.2 are the same or different and each is a hydrogen atom or a methyl group, R.sub.3 is a hydrogen atom, a hydroxyl group or a methoxy group, and R.sub.4 is a hydrogen atom or an amino group. The specification of this Japanese patent application pre-publication No. 7493/82 contains no reference to istamycin B at all, too. For the same reason as above, 3-demethoxy-2"-N-formimidoylistamycin B, the second new compound of this invention is distinguished from the known formimidoyl derivatives of a sporaricin (KA-6606II) which are exemplified in the above Japanese patent application pre-publication "Kokai" No. 7493/82, as this is discussed later in more detail.
Furthermore, we are aware of U.S. Pat. No. 4,353,893 of Watanabe et al (claiming the Convention priorities from both the aforesaid Japanese patent applications Nos. 67084/80 and 80842/80) which discloses the 5-demethoxy derivatives of some sporaricins and some sannamycins mentioned therein with regard to the aforesaid two Japanese patent application pre-publications and claims those of the formula ##STR5## wherein R.sub.1 and R.sub.2 are different and each represents a hydrogen atom or a methyl group, R.sub.3 represents a hydrogen atom, or a group represented by the formula-COCH.sub.2 NHR' in which R' is a member selected from the group consisting of a hydrogen atom, --CH.dbd.NH and ##STR6## and the symbol between the carbon atoms at the 5- and 6-positions represents a single or double bond.
Although the aminocyclitol rings are numbered in the opposite directions in U.S. Pat. No. 4,353,893 (as well in said two Japanese patent application pre-publications) and in the compounds disclosed and claimed therein (that is, compounds named 3-demethoxy derivatives herein are named as 5-demethoxy derivatives therein), it may be seen that the claims of U.S. Pat. No. 4,353,893 literally include within their scope the two compounds disclosed and claimed herein, i.e. 3-demethoxyistamycin B and 3-demethoxy-2"-N-formimidoylistamycin B of this invention. However, U.S. Pat. No. 4,353,893 does not exemplify either of these two compounds of this invention and, further neither discloses the starting material for the preparation of the 3-demethoxyistamycin B compounds of this invention, nor teaches how the necessary starting material may be prepared. Thus, the necessary starting material, 3-O-demethylistamycin B.sub.o used herein, and the 3-demethoxyistamycin B compounds produced herein are containing a 5'-methylaminomethyl group (--CH.sub.2 NHCH.sub.3) and a C-1 amino group which is present in the equatorial position in the aminocyclitol moiety and in the particular stereo configuration cis to the sugar moiety, and evidently the 3-O-demethylistamycin B.sub.o required as the starting material must contain the same groups and configurations, with bearing in mind that the necessary deoxygenation, namely removal of the hydroxyl group takes place only at the 3-position of the istamycin B.sub.o compound. On the other hand, U.S. Pat. No. 4,353,893 discloses as the starting materials only such 5-O-demethyl KA-6606 compounds (the 5-O-demethyl sporaricins) which contain a C-1 amino group that is present in the equatorial position in the aminocyclitol moiety and is cis to the sugar moiety, but of which all have a 5'-(.alpha.-amino)ethyl group (--CH(NH.sub.2)CH.sub.3); and such 5-O-demethyl KA-7038 compounds (the 5-O-demethyl sannamycins) some of which contain a 5'-methylaminomethyl group (--CH.sub.2 NHCH.sub.3), but of which all the sannamycin derivatives have a C-1 amino group which is trans to the sugar moiety. For these reasons, the 5-O-demethyl sporaricins and 5-O-demethyl sannamycins starting materials disclosed in U.S. Pat. No. 4,353,893 (as well as said Japanese patent application pre-publication Nos. 164197/81 and 7493/82) are, in fact, not suitable as the starting material to be employed in the production of any of the new two compounds of this invention disclosed and claimed herein, because they have the wrong 5'-substitution and/or the wrong stereo configuration of the 1-amino group. Besides, the 5-O-demethylsporaricins and 5-O-demethylsannamycins starting material disclosed in said U.S. patent are derived from the sporaricins and sannamycins which are all fermentatively produced, and they are not the chemically synthetic products, and hence said U.S. patent had no disclosure of how to obtain the necessary starting materials for the production of the new compounds disclosed and claimed herein. Thus, U.S. Pat. No. 4,353,893 as well as the aforesaid Japanese patent application pre-publications "Kokai" Nos. 164197/81 and 7493/82 do not have an enabling disclosure for the production of the necessary starting 3-O-demethylistamycin B.sub.o and the herein claimed 3-demethoxyistamycin B or 3-demethoxy-2"-N-formimidoylistamycin B of this invention.
In order to depict more clearly the differences in the steric structure and in the various substituents between the herein claimed new compounds of this invention and the prior art compounds of the above acknowledged publications, it will be worth to show that the 3-demethoxy derivatives of KA-6606 I (sporaricin A) and KA-7038 I (sannamycin A) as well as 3-demethoxyistamycin B of this invention have the following structures (see the "Journal of Antibiotics" 32, 173-179 (March 1979) and 32, 1066-1068 (October 1979); and the "Aminoglycoside Antibiotics" page 26, edited by H. Umezawa and I. R. Hooper, published from Springer-Verlag, 1982):
______________________________________ ##STR7## Ra Rb Rc Rd ______________________________________ 3-demethoxy KA 6606 I H NH.sub.2 CH.sub.3 H 3-demethoxy KA 7038 I NH.sub.2 H H CH.sub.3 3-demethoxyistamycin B H NH.sub.2 H CH.sub.3 ______________________________________
Accordingly, when the stereo structures of the herein claimed two new compounds of this invention are investigated fully and compared to those of the prior art compounds, it is evident that the herein claimed new compounds are differentiated from the prior art compounds, even if the above acknowledged publications show the general formulae which literally includes the herein claimed new two compounds of this invention.
The 3-demethoxyistamycin B and 3-demethoxy-2"-N-formimidoylistamycin B described and claimed herein have been disclosed by us in the Journal of Antibiotics, 36, pp. 331-334 (March 1983), along with details of their preparation and their antibacterial activity.